The clinical significance of human immunodeficiency virus type 1-associated paraproteins

We observed and characterized paraproteins present in the serum of seven human immunodeficiency virus type 1 (HIV-1)-infected individuals. Immunoglobulin (Ig) subclass typing performed on these paraproteins identified five as IgG1 kappa, one as an IgG3 lambda, and one as an IgA lambda. The IgG1 kappa paraproteins, purified by high-pressure liquid chromatography, contained the majority of anti-HIV-1 antibody reactivity present in the five serum specimens (ranging from 1:5,000 to 1:500,000) as demonstrated by immunoblot. All five IgG1 paraproteins had at least two light chain species as demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the antibodies were reactive with multiple HIV-1 viral antigens. In contrast, the electrophoretically purified IgG3 lambda and IgA lambda paraproteins did not react with HIV-1 antigens and only one light chain species was detected by SDS-PAGE. The subsequent clinical evaluation of these patients following the initial observation of paraproteinemias failed to correlate the presence of paraproteins with the development of lymphoma over a 2 to 3 year period. These data support the hypothesis that IgG1 paraproteins present in the sera of HIV-1 infected individuals reflect a normal albeit exuberant polyclonal immune response to HIV-1 viral antigens. In contrast, the clinical significance of an IgG3 lambda or an IgA lambda paraprotein is unclear at present.     

The immunoglobulin superantigen-binding site of HIV-1 gp120 activates human basophils

OBJECTIVE: To investigate the mechanism whereby HIV-1 envelope glycoprotein gp120 from four different isolates obtained in three different countries induces proinflammatory mediator release from normal human basophils. METHODS: Histamine, cysteinyl leukotriene C4 (LTC4) and interleukin 4 (IL-4) release into the supernatant was measured in gp120-stimulated peripheral blood basophils from HIV-1 and HIV-2 negative subjects. RESULTS: The HIV glycoprotein was a potent stimulus for release of these mediators in basophils purified from donors negative for HIV-1 and HIV-2. There was also a correlation (r = 0.58; P < 0.01) between the maximum IL-4 release from basophils induced by gp120 and by anti-IgE. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released histamine in response to gp120 and anti-IgE. Anti-IgE specifically desensitized basophils to a subsequent challenge with anti-IgE and gp120. Human monoclonal IgM carrying the VH3 domain, but not that carrying the VH6 domain, inhibited gp120-induced secretion of histamine from basophils in a concentration-dependent manner. Synthetic peptides identical to regions distant from the N- and C-termini of gp120MN inhibited its activating capacity. CONCLUSIONS: gp120 acts as a viral superantigen interacting with the VH3 domain of IgE to induce the release of preformed and de novo synthesized mediators from human cells carrying the Fc fragment Fc epsilonRI receptor.     

Characterization of molecular features, antigen-binding, and in vitro properties of IgG and IgM variants of 4E10, an anti-HIV type 1 neutralizing monoclonal antibody

The human monoclonal antibody 4E10 has been generated previously by immortalization of peripheral blood cells from an HIV-1-infected individual. This antibody binds to the linear epitope NWFDIT on gp41 and exhibits exceptional neutralizing activity against a broad spectrum of primary HIV-1 isolates. In the present study, molecular features, immunoreactivity, and functional activity of 4E10 were studied. The original hybridoma-derived 4E10 was of subtype IgG(3). Analysis of the variable segment of the heavy chain (VH) demonstrated extensive somatic mutations compared to the closest homologous germline gene VH1-69. Most amino acid substitutions occurred in the complementarity-determining region (CDR) 2, characteristic for an antigen-driven somatic maturation. The heavy chain of the CDR3 (H3) is of unusual length and cannot be attributed with certainty to any specific D(H) locus. To enable mass production and to prolong the in vivo half-life, 4E10 was subsequently cloned as IgG(1) in Chinese hamster ovary (CHO) cells. In additional studies, 4E10 was class switched to the IgM isotype. Binding to the linear epitope NWFDIT was not significantly changed after the cloning procedures. However, in vitro studies revealed dramatic differences in the neutralizing potential. The antiviral activity could be greatly enhanced by change of IgG(3) to IgG(1). In contrast, the IgM isotype almost completely lost its neutralizing potential.     

Sequestration of anti-platelet GPIIIa antibody in rheumatoid factor immune complexes of human immunodeficiency virus 1 thrombocytopenic patients.

Human immunodeficiency virus 1-related idiopathic thrombocytopenic purpura (HIV-1-ITP) patients have a 4-fold increased percentage of CD5+ B cells and a 4.8-fold increased percentage of serum immune complexes precipitated by polyethylene glycol (PEG-ICs) compared to control subjects, as reported previously. Since CD5+ B cells produce predominantly IgM rheumatoid factor (RF) vs. Fc of IgG and PEG-ICs contain high levels of IgM, we looked for the presence of RF in the immune complexes of HIV-1-ITP patients. PEG-ICs were adsorbed to protein A and dissociated with acid, and IgM and IgG were purified by gel filtration and affinity chromatography. Solid-phase ELISA was used to measure antibody specificity vs. platelets, Fc, and HIV-1 gp120, p24, and CD4. Dissociated IgG antibody reacted with platelets, HIV-1 gp120, p24, and CD4, but not with Fc. Serum IgG did not react with platelets or Fc but did react with HIV-1 gp120, p24, and CD4. Both PEG-IC IgM and serum IgM reacted with Fc as well as the other four antigens. Control IgM and IgG were unreactive. Isolated IgM from PEG-ICs relocated approximately 50% of the IgG preincubated with IgM to the Vo region of a G200 gel-filtration column. Anti-platelet IgG but not IgM could be affinity-purified from fixed platelets. Both F(ab')2 fragments of anti-platelet IgG and the total PEG-IC bound to platelets in a saturation-dependent manner. F(ab')2 of anti-platelet IgG inhibited 50% binding of PEG-IC to platelets at an F(ab')2/complex ratio of 3:1 (wt/wt). Scatchard analysis revealed two classes of binding sites: high-affinity Kd values of 0.8-1.8 nM and lower-affinity Kd values of 6.6-12.3 nM with respective numbers of binding sites of 44,000-57,000 and 122,000-256,000 (n = 4). Anti-platelet IgG of 6/6 patients precipitated GPIIIa from platelet lysates of surface 125I-labeled platelets. Platelet count correlated inversely with anti-platelet IgG (r = -0.73; P < 0.01; n = 27). Thus, PEG-ICs of HIV-1-ITP patients contain IgM RF, which sequesters serum anti-platelet IgG containing anti-GPIIIa. Anti-platelet IgG contributes to binding of immune complexes to platelets and correlates with thrombocytopenia.     

Amino acid sequence of the variable region of a human mu chain: location of a possible JH segment.

The complete amino acid sequence of th variable (V) region of the mu heavy chain of a human IgM immunoglobulin (Cam) has been determined. The strategy for sequence determination involved sequenator analysis of the CNBr cleavage products of the succinylated carboxymethylated Fab mu fragment, and of tryptic peptides of the CNBr polypeptides and thermolytic subpeptides. The variable region of this heavy chain (VH) belongs to the VHIII subgroup; it has greater than 70% homology with other VHIII sequences and contains the VHIII marker peptide, Phe-Thr-Ile-Ser-Arg (residues 67-71). As more sequences have been published, the number of subgroup-specific residues has diminished to the point that no position is absolutely subgroup specific. An analysis of the available human VH sequences in the V/C switch region showed the likelihood of a human JH segment (residues 101-113) analogous to the J segments in mouse light chains. The JH region is highly conserved, has striking homology to proposed mouse JH regions, and has significant homology to known mouse J lambda and J kappa segments.     

THE Ig CLASS AND LIGHT CHAIN TYPE OF THE LONG ACTING THYROID STIMULATOR

The Ig class and light chain type of LATS has been examined. Serum samples containing high levels of LATS were assayed before and after incubation with specific antisera to IgG, IgA and IgM, and kappa and lambda light chains. It was found that LATS activity was restricted to the IgG class of immunoglobulins and that the LATS activity was distributed approximately equally between the kappa and lambda type of IgG. These results are consistent with a polyclonal origin for LATS.     

Functional activity of an HIV-1 neutralizing IgG human monoclonal antibody: ADCC and complement-mediated lysis.

The IgG1 kappa, human monoclonal antibody (HMAb), F105, was studied for functional activity in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). F105 reacts with a discontinuous epitope on the CD4 binding site of the HIV-1 envelope glycoprotein, gp120, expressed on the surfaces of infected cells and neutralizes diverse viral strains at antibody concentrations readily achievable in humans. Neither F105 nor serum (diluted 1:50) from HIV seropositive donors mediate CDC against an SF2-infected cell line with rabbit or human sera as a source of complement. F105 and HIV-1 sera mediate ADCC against the SF2 strain. Normal human serum reduced spontaneous lysis of SF2 by peripheral blood monocytes (PBM). Although mixing of F105 with normal human serum reduced the lysis observed (36 +/- 8 vs. 42 +/- 8%), this still was significantly greater than lysis in media (30 +/- 5%) or normal human serum (23 +/- 6%) (p less than .05). A murine antibody to CD16 significantly reduced spontaneous lysis observed with media (30 +/- 5 vs. 18 +/- 3%) while normal mouse serum had no effect (31 +/- 7%). ADCC mediated by F105 is completely abrogated by the anti-CD16 antibody (42 +/- 8 vs. 22 +/- 4%), while only a fraction of ADCC mediated by HIV sera is inhibited by anti-CD16 (60 +/- 9 vs. 46 +/- 6%), suggesting that several populations of effector cells function in ADCC mediated by the polyclonal sera. Thus, F105, as opposed to polyclonal sera, mediates ADCC through a CD16+ PBM population.     

Analysis of autoimmune bone marrow by antibody-phage display: somatic mutations and third complementarity-determining region arginines in anti-DNA gamma and kappa V genes

OBJECTIVE: To examine anti-double-stranded DNA (anti-dsDNA) IgG autoantibodies from the bone marrow of individuals with systemic lupus erythematosus (SLE). METHODS: A library of single-chain variable fragments (scFv) was constructed from SLE bone marrow complementary DNA of gamma, kappa, and lambda isotype by cloning into the pHENIX phagemid vector. The library was screened with dsDNA in solution, and 2 anti-DNA phage, DNA1 and DNA4, were isolated and their Ig V genes sequenced. Soluble scFv corresponding to DNA1 and DNA4, and their heavy (H)- and light (L)-chain recombinants, were prepared, purified, and analyzed for binding to DNA by enzyme-linked immunosorbent assay. RESULTS: DNA1 and DNA4 used different Ig H-chain (3-30 and 5-51, respectively) and L-chain (DPK15 and DPK22, respectively) V genes. The ratios of replacement mutations to silent mutations in DNA1 and DNA4 suggest that their V genes were selected for improved antigen binding in vivo. The recombinant between DNA4VH and DNA1VL showed the highest relative affinity for both single-stranded DNA and dsDNA. These 2 Ig subunits contained third complementarity-determining region arginines and had acquired the majority of replacement mutations. CONCLUSION: Anti-dsDNA IgG autoantibodies from the bone marrow of SLE patients exploit diverse V genes and cationic V-D-J and V-J junctions for DNA binding, and accumulate replacement mutations that enhance binding.     

Diversity and plasticity of the anti-DNA topoisomerase I autoantibody response in scleroderma

OBJECTIVE: To examine domain recognition by anti-DNA topoisomerase I (anti-DNA topo I, or anti-topo I) antibodies over time in scleroderma patients. METHODS: Serial serum samples from scleroderma patients with known reactivity to Scl-70, a 70-kd topo I breakdown product, were tested by immunoblot for IgM, IgG, IgA, kappa, and lambda reactivity to Scl-70 and 8 overlapping recombinant peptide fragments (F1-F8) that span the human topo I molecule. RESULTS: IgM, IgG, kappa, and lambda anti-topo I antibodies in both early-disease and late-disease serum samples preferentially recognized the Scl-70 molecule rather than the F1-F8 peptides, suggesting preferential recognition of conformational determinants on Scl-70 throughout the disease course. Amounts of both primary and secondary anti-topo I antibodies to Scl-70 varied over time, including increases in primary antibody responses late in the disease course. Striking variability in recognition of the F1-F8 peptides by IgM, IgG, IgA, kappa, and lambda anti-topo I antibodies was seen in serial samples. Most often, the change in FI-F8 recognition from one sample to the next was unpredictable, although occasionally patterns of antibody recognition were reciprocal in serial samples. Of note, in several patients, what could have been interpreted as domain spreading among F1-F8 in 2 successive samples was just a part of changing antibody reactivity to these peptides that again became more restricted in a third sample. CONCLUSION: Titers and immunodominant domains recognized by both primary and secondary anti-topo I antibodies are highly variable over time. This suggests continual antigen presentation and regulation of the anti-topo I antibody response in scleroderma, even late in the disease course.     

Analysis of HIV type 1 gp41 sequences in diverse HIV type 1 strains

The HIV fusion inhibitor enfuvirtide (ENF/Fuzeon) targets the env gp41 transmembrane domain. Mutations in gp41 are associated with ENF resistance. We developed a prototype assay to genotype a 676-bp region spanning the heptad repeat domains (HR1 and HR2) of HIV-1 gp41. Plasma samples were collected from 126 HIV-1-infected blood donors in Cameroon, Brazil, Uganda, South Africa, Thailand, and Argentina. Based on analysis of gag p24, pol integrase, and env gp41 genes, the panel was composed of subtypes A/A2 (18), B (11), C (14), D (10), F/F2 (9), G (7), CRF01_AE (9), CRF02_AG (33), and recombinant strains (15). Genotyping was successful for 119 of the 126 samples (94.4%). Although numerous amino acid polymorphisms were detected in some samples, none had primary mutations associated with ENF resistance. The gp41 HIV-1 research reagents developed by Celera are useful tools for genotyping analysis of the gp41 region in diverse HIV-1 strains.     

Immunoglobulin V genes in rheumatoid arthritis.

Recent studies have revealed that a broad spectrum of Ig V genes (VH, V kappa, V lambda) contribute to the rheumatoid factor (RF) and non-RF produced by B cells in patients with rheumatoid arthritis (RA). This result contrasts with the restricted V gene use of paraprotein IgM RF. Certain VH and VL genes, however, appear more often in RA than expected from random expression, including some of the paraprotein-associated V genes. Many V genes expressed in RA are the same as those found in the fetal/CD5+ repertoire, suggesting an important role for CD5+ B cells in RA. Somatic mutations suggest that the B-cell response in RA is at least in part antigen-driven, although many Ig in RA have little or no mutation. Improved detection of V-gene polymorphisms now enable study of Ig V gene RFLP in RA.     

Normalization of serum-free light chains in patients with systemic lupus erythematosus upon rituximab treatment and correlation with biological disease activity

Increased free light chain (FLC) levels have been reported as useful in various autoimmune conditions. We investigated how FLC concentrations change upon B cell targeted therapy in systemic lupus erythematosus (SLE) patients and if they correlate with disease activity. We retrospectively studied 11 SLE patients without renal failure, whom were treated with rituximab. Quantitative determination of IgG, IgA, IgM, and serum FLC was performed before and after rituximab. At baseline, 70% had abnormal serum FLC levels, including increased kappa and lambda levels, while the kappa/lambda ratio was normal for all. A strong correlation was observed between complement C3 fraction and kappa levels (r = -0.929, P < 0.001) or lambda levels (r = -0.854, P = 0.003), but not with IgG, IgA, or IgM levels. After rituximab treatment, kappa and lambda FLC concentrations decreased significantly whilst total concentrations of IgG, IgA, and IgM also decreased but remained within the normal range. There was a strong correlation only between kappa FLC levels and complement C3 fraction consumption (r = -0.543, P = 0.003). In SLE patients without renal failure, increased FLC levels (mainly kappa) with normal kappa/lambda ratios are a common feature, and in contrast to total IgG levels, FLC concentrations correlate with biological disease activity.     

VH and VL gene analysis in sporadic Burkitt's lymphoma shows somatic hypermutation, intraclonal heterogeneity, and a role for antigen selection

Tumor cell lines and one tumor biopsy from seven cases of Epstein-Barr virus (EBV) genome-negative sporadic Burkitt's lymphoma (BL) have been investigated for usage and mutational pattern of Ig variable region genes. The VH genes were derived from the VH 3 (one) and VH4 (six) families and both the IgM-positive (six) and the IgA-positive (one) were all mutated from their germline counterparts. The VL genes were derived from V kappa 1 (one), V kappa 3 (one), V lambda 1 (four), and V lambda 2 (one) families and were also somatically hypermutated. Biopsy material from one of the IgM-positive cases showed VH and VL sequences that matched the derived cell line, with additional intraclonal sequence heterogeneity, indicating that the tumor cells had undergone posttranformation somatic mutation. Mutational patterns in V(H) genes did not show a conventional role for antigen in selecting tumor cell sequences. In contrast, patterns in VL sequences were consistent with a role for antigen in five of seven cases. The pattern of extensive scattered somatic hypermutation and intraclonal variation is similar to that in VH sequences of EBV genome-positive endemic BL, although the degree of mutational activity is less. These common features indicate that B cells involved in the two variants of BL may share a common clonal history.     

V gene usage by seven hybrids derived from CD5+ B-cell chronic lymphocytic leukemia and displaying autoantibody activity

We report here the complete heavy and light chain variable region sequences of seven heterohybridomas derived from CD5+ chronic lymphocytic leukemia (CLL) B lymphocytes and displaying natural autoantibody activity. The three hybrids displaying a polyreactive pattern of binding used VH4 family members, ie, the VH4-18 gene in germinal configuration in two cases and a VH4 gene with 90% homology with VH4-21 for the third one. A hybrid expressing anti-Sm activity used a VH3 family member with 95.26% homology with the 30P1 gene. The three hybrids exclusively displaying rheumatoid factor activity expressed VH1 family genes: 51P1 gene for two (in germinal configuration in one, and with 93.2% homology in the other), whereas the third one used the V1-3b gene (98.8% homology). Definitive homology with known germline D segments was found for four of the seven hybrids (DN2 in 3 and DLR4 in 1) and JH use appeared to be random. The three hybrids displaying polyreactive activity expressed V kappa I, V lambda III, and V lambda II genes, all in germinal configuration. Among the three hybrids with rheumatoid factor activity, two used the same V kappa II gene with, respectively, 98% and 96% homology with a gene previously described; the third used a V lambda I gene in germinal configuration. Finally, the clone with anti-Sm activity used a V lambda III gene having 97% homology with a germinal gene. Overall, these results attempt to establish the relationship between frequent self- reactivity observed in CD5+ B-CLL and V gene usage. For VH genes, they confirm overexpression of the 51P1 gene in B-CLL and suggest nonstochastic use of two VH4 genes (4-21 and 4-18). For VL genes, available information is too scarce to lead to firm conclusions.     

Human monoclonal anti-cytomegalovirus antibodies

Specific human monoclonal anti-CMV antibodies have been isolated and characterized. The first patient had a chronic T cell lymphocytic leukaemia and a subclinical CMV infection developed at the same time as a monoclonal peak of kappa IgG3. The purified F (ab')2 fragment of the IgG3 had an intense anti-CMV activity. A second monoclonal antibody, also a kappa IgG3, was isolated in a non-immunodepressed patient with a primary CMV infection (chronic pyrexia and hepatitis). The immunotransfer showed that the anti-CMV IgM and IgG of the patient's serum reacted particularly with the p51 protein of virus capsid. The monoclonal IgG3 was specific for the same p51. The third monoclonal anti-CMV Ig studied was synthesized in vitro by the B lymphocytes of a renal transplant patient immortalized by the Epstein-Barr virus. This kappa IgM produced continuously reacted strongly with the nucleus of the cells infected by the CMV. Human monoclonal anti-CMV antibodies could be used for the early detection of viral antigens by immunofluorescence and might also be used to treat severe cases of CMV infection.     

Detection of cross-reacting idiotypes in sera of lymphoma patients by inverse monoclonal radioimmunoassay

An anti-idiotypic IgG1 kappa murine monoclonal antibody (MoAb) Y7 against purified monoclonal IgM lambda 1, derived from a patient with Waldenstr?m's macroglobulinemia, has been generated. This antibody cross-reacted with the tumor-derived idiotypes of patients with B cell non Hodgkin's lymphoma as measured by competitive inverse solid radioimmunoassay using unpurified serum samples. Our results with the inhibition curves of 10 sera of normal donors and 60 sera of lymphoma patients indicate that 21 lymphoma patients revealed cross-reactivities greater than 7%, the mean value observed in normal donors. Of these, 5 sera cross-reacted strongly, in the range of 43-163%, revealing a frequency of positive cross-reactivity for MoAb Y7 of 1/12 sera of lymphoma patients. The generation of a panel of anti-idiotypic antibodies which cross-react with different tumor-derived Ig in serum may be valuable for monitoring the disease in a high proportion of NHL patients.     

Quantitation of immunoglobulin classes and subclasses in anti-Rh (D) antibodies

The isotype profiles of anti-Rh (D) antibodies were measured from 16 serum samples with a solid-phase radioimmunoassay that employed monoclonal anti-isotype antibodies. These antibodies had been standardized in another solid-phase system with the aid of monoisotypic antibodies (e.g., anti-tetanus toxoid of isotype IgG4), and this permitted calculations of the relative concentrations of different isotypes in each anti-D population. Of the heavy-chain isotypes, only IgG1 and IgG3 were found in anti-Rh (D) antibodies. The share of IgG1 varied from 100% (2 sera) to 0% (1 serum) of detected units, and the mean proportion was 73.8%. The remainder was IgG3 (mean share 26.2%). The proportions of kappa and lambda immunoglobulins varied greatly in individual sera, in three sera only kappa Ig and in one serum only lambda Ig could be detected.     

High frequency of recombinant genomes in HIV type 1 samples from Brazilian southeastern and southern regions

We describe the genetic variability of HIV-1 subtypes and recombinant genomes in samples from southeastern and southern Brazilian regions. Phylogenetic analysis of a subset of 34 samples (8F, 7B, 7C, 2D, 1A, and 9 B" variant) based on the DNA sequencing of the env gp120 and gp41, gag p17, and nef regions confirmed the presence of nine (26.5%) potentially HIV-1 recombinant genomes. From the eight C2-V3 gp120 subtype F samples, only two seem to be pure F. One of the samples, classified as B" in the C2-V3 gp120 and as B in gp41 had the gag and nef regions clustering with subtype C. Two of seven C2-V3 subtype C samples presented distinct recombinant patterns as Bgag/Cenv/Bnef and Bgag/Cenv/Cnef. Putative recombinant breakpoints were obtained for three samples presenting discordant subtypes (F/B) between gp120 and gp41 env fragments showing that similar breakpoints could be observed between two unlinked samples (95BRRJ014 and 96BRRJ101). A higher degree of polymorphism was verified in the analysis of a subtype A sample (98BRRS058) in the C2-V3/gp41 env fragment. The intrasubtype C distance was found to be lower than that found for the other subtypes for all genomic regions. These data confirm that distinct HIV-1 subtypes and recombinant forms are actively participating in the Brazilian AIDS epidemic, and that the subtype C was introduced more recently into southern Brazil.     

Isotype modulates epitope specificity, affinity, and antiviral activities of anti-HIV-1 human broadly neutralizing 2F5 antibody

The constant heavy chain (CH1) domain affects antibody affinity and fine specificity, challenging the paradigm that only variable regions contribute to antigen binding. To investigate the role of the CH1 domain, we constructed IgA2 from the broadly neutralizing anti-HIV-1 2F5 IgG1, and compared 2F5 IgA2 and IgG binding affinity and functional activities. We found that 2F5 IgA2 bound to the gp41 membrane proximal external region with higher affinity than IgG1. Functionally, compared with IgG1, 2F5 IgA2 more efficiently blocked HIV-1 transcytosis across epithelial cells and CD4(+) cell infection by R5 HIV-1. The 2F5 IgG1 and IgA2 acted synergistically to fully block HIV-1 transfer from Langerhans to autologous CD4(+) T cells and to inhibit CD4(+) T-cell infection. Epitope mapping performed by screening a random peptide library and in silico docking modeling suggested that along with the 2F5 IgG canonical ELDKWA epitope on gp41, the IgG1 recognized an additional 3D-conformational epitope on the gp41 C-helix. In contrast, the IgA2 epitope included a unique conformational motif on the gp41 N-helix. Overall, the CH1 region of 2F5 contributes to shape its epitope specificity, antibody affinity, and functional activities. In the context of sexually transmitted infections such as HIV-1/AIDS, raising a mucosal IgA-based vaccine response should complement an IgG-based vaccine response in blocking HIV-1 transmission.     

Anti-IgG antibodies from sera of healthy individuals neutralize HIV-1 primary isolates

Immunoglobulins (Ig) of pooled healthy human sera were purified by affinity chromatography based on their reactivity with human IgG. This Ig fraction represent connected, natural antibodies (NAbs) and here are denoted as anti-IgG antibodies. The data revealed that IgG, IgA and IgM isotypes are constituents of anti-IgG fraction. The ability of anti-IgG antibodies to prevent infection of PBMC by HIV-1 was demonstrated. They exhibited different neutralizing activity depending on the phenotype of the tested virus. The efficacy of neutralization was comparable to monoclonal antibodies (MAbs) IgG1b12 at least for the HIV-1 (92HT593B) strain. These studies suggest that connected antibodies thus, constituents of immune network, could prevent infection by HIV-1. NAbs as essential components of therapeutic molecules of intravenous Ig (IVIg) have a beneficial effect on variety of immunological disorders by affecting the structure, function and dynamics of the immune network. Since, hallmark of HIV-1 infection are immunological disorders we hypothesizes that they might be corrected to some extend by anti-IgG antibodies.